tbuckley/cabot-search huggingface dataset:
Comparing methods for constructing and representing human pangenome graphs
Authors: Francesco Andreace, Pierre Lechat, Yoann Dufresne, Rayan Chikhi
Journal: Genome biology (2023)

Abstract Background As a single reference genome cannot possibly represent all the variation present across human individuals, pangenome graphs have been introduced to incorporate population diversity within a wide range of genomic analyses. Several data structures have been proposed for representing collections of genomes as pangenomes, in particular graphs. Results In this work, we collect all publicly available high-quality human haplotypes and construct the largest human pangenome graphs to date, incorporating 52 individuals in addition to two synthetic references (CHM13 and GRCh38). We build variation graphs and de Bruijn graphs of this collection using five of the state-of-the-art tools: , , , and . We examine differences in the way each of these tools represents variations between input sequences, both in terms of overall graph structure and representation of specific genetic loci. Conclusion This work sheds light on key differences between pangenome graph representations, informing end-users on how to select the most appropriate graph type for their application.
Bimetallic nanoparticles as cascade sensitizing amplifiers for low-dose and robust cancer radio-immunotherapy
Authors: Yupeng Wang, Lina Wang, Tao Li, Min Ouyang, Hejian Xiong, Dongfang Zhou
Journal: Acta Pharmaceutica Sinica B (2023)

Radiotherapy (RT) is one of the most feasible and routinely used therapeutic modalities for treating malignant tumors. In particular, immune responses triggered by RT, known as radio-immunotherapy, can partially inhibit the growth of distantly spreading tumors and recurrent tumors. However, the safety and efficacy of radio-immunotherapy is impeded by the radio-resistance and poor immunogenicity of tumor. Herein, we report oxaliplatin(IV)-iron bimetallic nanoparticles (OXA/Fe NPs) as cascade sensitizing amplifiers for low-dose and robust radio-immunotherapy. The OXA/Fe NPs exhibit tumor-specific accumulation and activation of OXA(II) and Fe2+ in response to the reductive and acidic microenvironment within tumor cells. The cascade reactions of the released metallic drugs can sensitize RT by inducing DNA damage, increasing ROS and O2 levels, and amplifying the immunogenic cell death (ICD) effect after RT to facilitate potent immune activation. As a result, OXA/Fe NPs-based low-dose RT triggered a robust immune response and inhibited the distant and metastatic tumors effectively by a strong abscopal effect. Moreover, a long-term immunological memory effect to protect mice from tumor rechallenging is observed after a single treatment. Overall, the bimetallic NPs-based cascade sensitizing amplifier system offers an efficient radio-immunotherapy regimen that addresses the key challenges.
Neuronal and synaptic adaptations underlying the benefits of deep brain stimulation for Parkinson's disease
Authors: Wenying Xu, Jie Wang, Xin-Ni Li, Jingxue Liang, Lu Song, Yi Wu, Zhenguo Liu, Bomin Sun, Wei-Guang Li
Journal: Translational Neurodegeneration (2023)

Abstract Deep brain stimulation (DBS) is a well-established and effective treatment for patients with advanced Parkinson's disease (PD), yet its underlying mechanisms remain enigmatic. Optogenetics, primarily conducted in animal models, provides a unique approach that allows cell type- and projection-specific modulation that mirrors the frequency-dependent stimulus effects of DBS. Opto-DBS research in animal models plays a pivotal role in unraveling the neuronal and synaptic adaptations that contribute to the efficacy of DBS in PD treatment. DBS-induced neuronal responses rely on a complex interplay between the distributions of presynaptic inputs, frequency-dependent synaptic depression, and the intrinsic excitability of postsynaptic neurons. This orchestration leads to conversion of firing patterns, enabling both antidromic and orthodromic modulation of neural circuits. Understanding these mechanisms is vital for decoding position- and programming-dependent effects of DBS. Furthermore, patterned stimulation is emerging as a promising strategy yielding long-lasting therapeutic benefits. Research on the neuronal and synaptic adaptations to DBS may pave the way for the development of more enduring and precise modulation patterns. Advanced technologies, such as adaptive DBS or directional electrodes, can also be integrated for circuit-specific neuromodulation. These insights hold the potential to greatly improve the effectiveness of DBS and advance PD treatment to new levels.
Regression of Liver Fibrosis in Patients on Hepatitis B Therapy Is Associated With Decreased Liver-Related Events
Authors: Yameng Sun, Wei Chen, Shuyan Chen, Xiaoning Wu, Xinxin Zhang, Lingyi Zhang, Hong Zhao, Mingyi Xu, Yongpeng Chen, Hongxin Piao, Ping Li, Lei Li, Wei Jiang, Xiaodong Li, Huichun Xing, Xudong Liu, Yuxi Zhang, Bingqiong Wang, Jialing Zhou, Tongtong Meng, Xinyan Zhao, Chen Shao, Yuanyuan Kong, Xinyu Zhao, Xiaojuan Ou, Chenghai Liu, Jidong Jia, Hong You
Journal: Clinical Gastroenterology and Hepatology (2023)
Cardiovascular Safety of Ozanimod in Patients With Ulcerative Colitis: True North and Open-Label Extension Analyses
Authors: Alessandro Armuzzi, Raymond K. Cross, Gary R. Lichtenstein, Jason Hou, Parakkal Deepak, Miguel Regueiro, Douglas C. Wolf, Lucy Akukwe, Harris A. Ahmad, Anjali Jain, Marc Kozinn, Hsiuanlin Wu, AnnKatrin Petersen, Lorna Charles, Millie Long
Journal: Clinical Gastroenterology and Hepatology (2023)

Evaluating cardiovascular safety of sphingosine 1-phosphate (S1P) receptor modulators is warranted due to S1P receptor expression on cardiomyocytes and vascular endothelial cells. This analysis reports the cardiovascular safety of ozanimod, an S1P receptor modulator, in patients with moderately to severely active ulcerative colitis from the phase 3 True North (TN) and open-label extension (OLE).
Preoperative chemotherapy, radiotherapy and surgical decision-making in patients with borderline resectable and locally advanced pancreatic cancer
Authors: Thomas F. Stoop, Rutger T. Theijse, Leonard W. F. Seelen, Bas Groot Koerkamp, Casper H. J. van Eijck, Christopher L. Wolfgang, Geertjan van Tienhoven, Hjalmar C. van Santvoort, I. Quintus Molenaar, Johanna W. Wilmink, Marco Del Chiaro, Matthew H. G. Katz, Thilo Hackert, Marc G. Besselink
Journal: Nature Reviews Gastroenterology & Hepatology (2023)
RAB27B-regulated exosomes mediate LSC maintenance via resistance to senescence and crosstalk with the microenvironment
Authors: Ying Chen, Jin Wen, Qian Li, Danyue Peng, Chenxi Liao, Xiao Ma, Mengyuan Wang, Jialan Niu, Di Wang, Yingnan Li, Xiaolan Zhang, Hao Zhou, Jing Zou, Lei Li, Lingbo Liu
Journal: Leukemia (2023)
Long-acting inhaled medicines: Present and future
Authors: Chengqian Zhang, Davide D'Angelo, Francesca Buttini, Mingshi Yang
Journal: Advanced Drug Delivery Reviews (2023)

Inhaled medicines continue to be an essential part of treatment for respiratory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. In addition, inhalation technology, which is an active area of research and innovation to deliver medications via the lung to the bloodstream, offers potential advantages such as rapid onset of action, enhanced bioavailability, and reduced side effects for local treatments. Certain inhaled macromolecules and particles can also end up in different organs via lymphatic transport from the respiratory epithelium. While the majority of research on inhaled medicines is focused on the delivery technology, particle engineering, combination therapies, innovations in inhaler devices, and digital health technologies, researchers are also exploring new pharmaceutical technologies and strategies to prolong the duration of action of inhaled drugs. This is because, in contrast to most inhaled medicines that exert a rapid onset and short duration of action, long-acting inhaled medicines (LAIM) improve not only the patient compliance by reducing the dosing frequency, but also the effectiveness and convenience of inhaled therapies to better manage patients' conditions. This paper reviews the advances in LAIM, the pharmaceutical technologies and strategies for developing LAIM, and emerging new inhaled modalities that possess a long-acting nature and potential in the treatment and prevention of various diseases. The challenges in the development of the future LAIM are also discussed where active research and innovations are taking place.
GenIA, the Genetic Immunology Advisor database for inborn errors of immunity
Authors: Andrés Caballero-Oteyza, Laura Crisponi, Xiao P. Peng, Kevin Yauy, Stefano Volpi, Stefano Giardino, Alexandra F. Freeman, Bodo Grimbacher, Michele Proietti
Journal: Journal of Allergy and Clinical Immunology (2023)

To date, no publicly accessible platform has captured and synthesized all of the layered dimensions of genotypic, phenotypic, and mechanistic information published in the field of inborn errors of immunity (IEIs). Such a platform would represent the extensive and complex landscape of IEIs and could increase the rate of diagnosis in patients with a suspected IEI, which remains unacceptably low.
IPEX syndrome from diagnosis to cure, learning along the way
Authors: Rosa Bacchetta, Maria Grazia Roncarolo
Journal: Journal of Allergy and Clinical Immunology (2023)

In the past 2 decades, a significant number of studies have been published describing the molecular and clinical aspects of immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome. These studies have refined our knowledge of this rare yet prototypic genetic autoimmune disease, advancing the diagnosis, broadening the clinical spectrum, and improving our understanding of the underlying immunologic mechanisms. Despite these advances, Forkhead box P3 mutations have devastating consequences, and treating patients with IPEX syndrome remains a challenge, even with safer strategies for hematopoietic stem cell transplantation and gene therapy becoming a promising reality. The aim of this review was to highlight novel features of the disease to further advance awareness and improve the diagnosis and treatment of patients with IPEX syndrome.
TRPV1-positive sensory nerves and neuropeptides are involved in epidermal barrier repair after tape stripping in mice
Authors: Kenji Usui, Chisa Nakashima, Sonoko Takahashi, Takaharu Okada, Yoshihiro Ishida, Saeko Nakajima, Akihiko Kitoh, Takashi Nomura, Teruki Dainichi, Tetsuya Honda, Rumi Katsumoto, Noriko Konishi, Mutsuyoshi Matsushita, Atsushi Otsuka, Kenji Kabashima
Journal: Journal of Allergy and Clinical Immunology (2023)
CAR-T Cell Therapy Shows Similar Efficacy and Toxicity in Patients With DLBCL Regardless of CNS Involvement
Authors: Evgenii Shumilov, Hristo Boyadzhiev, Paolo Mazzeo, Dilara Akhoundova, Michael Daskalakis, Urban Novak, Georg Lenz, Ulrike Bacher, Thomas Pabst
Journal: HemaSphere (2023)

Efficacy and toxicity of chimeric antigen receptor T (CAR-T) cell therapy in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) with central nervous system (CNS) involvement remain understudied. Here we analyzed the outcomes of CAR-T cell therapy in r/r DLBCL patients with CNS involvement and compared them with patients without CNS disease. Retrospective and monocentric comparative analysis of patient cohort with r/r DLBCL treated with CAR-T cell therapy: 15 patients with CNS versus 65 patients without CNS involvement. Overall response rates (80% versus 80%; P = 1.0), progression-free survival (P = 0.157), and overall survival (P = 0.393) were comparable for both cohorts. The frequency of cytokine release syndrome was comparable in the CNS and non-CNS cohorts; 93% versus 80%; P = 1.0. Numerically, immune effector-cell-associated neurotoxicity syndrome (all grades) was more frequent in patients with CNS manifestation (53% versus 29%; P = 0.063), although no grade 4 events were documented. Our study suggests that CAR-T cell therapy is effective and feasible in patients with r/r DLBCL and CNS manifestation.
CAR-modified Cellular Therapies in Chronic Lymphocytic Leukemia: Is the Uphill Road Getting Less Steep?
Authors: Candida Vitale, Valentina Griggio, Francesca Perutelli, Marta Coscia
Journal: HemaSphere (2023)

The clinical development of chimeric antigen receptor (CAR) T-cell therapy has been more challenging for chronic lymphocytic leukemia (CLL) compared to other settings. One of the main reasons is the CLL-associated state of immune dysfunction that specifically involves patient-derived T cells. Here, we provide an overview of the clinical results obtained with CAR T-cell therapy in CLL, describing the identified immunologic reasons for the inferior efficacy. Novel CAR T-cell formulations, such as lisocabtagene maraleucel, administered alone or in combination with the Bruton tyrosine kinase inhibitor ibrutinib, are currently under investigation. These approaches are based on the rationale that improving the quality of the T-cell source and of the CAR T-cell product may deliver a more functional therapeutic weapon. Further strategies to boost the efficacy of CAR T cells should rely not only on the production of CAR T cells with an improved cellular composition but also on additional changes. Such alterations could include (1) the coadministration of immunomodulatory agents capable of counteracting CLL-related immunological alterations, (2) the design of improved CAR constructs (such as third- and fourth-generation CARs), (3) the incorporation into the manufacturing process of immunomodulatory compounds overcoming the T-cell defects, and (4) the use of allogeneic CAR T cells or alternative CAR-modified cellular vectors. These strategies may allow to develop more effective CAR-modified cellular therapies capable of counteracting the more aggressive and still incurable forms of CLL.
Long-term outcome of co-infection of COVID-19 and tuberculosis: the “cursed duet”
Authors: Roland Diel, Neil W. Schluger
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>Due to synergistic negative effects, in TB/COVID-19 co-infected patients treatment outcome was starkly unfavourable when COVID-19 was diagnosed before or during TB treatment compared to patients having finished treatment prior to COVID-19 infection</b>https://bit.ly/3sCXOps
Leukocyte telomere length: the dawn of a new era of personalised medicine in fibrotic interstitial lung diseases?
Authors: Vincent Cottin, Martin Kolb
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>Leukocyte telomere length will be a biomarker applied to precision medicine. When &lt;10th percentile, it is associated with increased risk of mortality in patients with fibrotic hypersensitivity pneumonitis or unclassifiable ILD exposed to immunosuppression.</b>https://bit.ly/46TwAtv
An attack of asthma is not an attack of the heart: clarifying causal links between asthma and incident coronary heart disease
Authors: Caitlin Morgan, Daniel Higbee
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>Use of robust epidemiological methods to explore the fundamental causal relationship between asthma and incident coronary heart disease has found no association</b>https://bit.ly/3un6zES
Genome-wide prediction of pathogenic gain- and loss-of-function variants from ensemble learning of a diverse feature set
Authors: David Stein, Meltem Ece Kars, Yiming Wu, Çiğdem Sevim Bayrak, Peter D. Stenson, David N. Cooper, Avner Schlessinger, Yuval Itan
Journal: Genome Medicine (2023)

Gain-of-function (GOF) variants give rise to increased/novel protein functions whereas loss-of-function (LOF) variants lead to diminished protein function. Experimental approaches for identifying GOF and LOF are generally slow and costly, whilst available computational methods have not been optimized to discriminate between GOF and LOF variants. We have developed LoGoFunc, a machine learning method for predicting pathogenic GOF, pathogenic LOF, and neutral genetic variants, trained on a broad range of gene-, protein-, and variant-level features describing diverse biological characteristics. LoGoFunc outperforms other tools trained solely to predict pathogenicity for identifying pathogenic GOF and LOF variants and is available at https://itanlab.shinyapps.io/goflof/ .
STmut: a framework for visualizing somatic alterations in spatial transcriptomics data of cancer
Authors: Limin Chen, Darwin Chang, Bishal Tandukar, Delahny Deivendran, Joanna Pozniak, Noel Cruz-Pacheco, Raymond J. Cho, Jeffrey Cheng, Iwei Yeh, Chris Marine, Boris C. Bastian, Andrew L. Ji, A. Hunter Shain
Journal: Genome biology (2023)

Spatial transcriptomic technologies, such as the Visium platform, measure gene expression in different regions of tissues. Here, we describe new software, STmut, to visualize somatic point mutations, allelic imbalance, and copy number alterations in Visium data. STmut is tested on fresh-frozen Visium data, formalin-fixed paraffin-embedded (FFPE) Visium data, and tumors with and without matching DNA sequencing data. Copy number is inferred on all conditions, but the chemistry of the FFPE platform does not permit analyses of single nucleotide variants. Taken together, we propose solutions to add the genetic dimension to spatial transcriptomic data and describe the limitations of different datatypes.
The role of extracellular vesicles in circulating tumor cell-mediated distant metastasis
Authors: Siyin Guo, Jing Huang, Genpeng Li, Wenjie Chen, Zhihui Li, Jianyong Lei
Journal: Molecular Cancer (2023)

Current research has demonstrated that extracellular vesicles (EVs) and circulating tumor cells (CTCs) are very closely related in the process of distant tumor metastasis. Primary tumors are shed and released into the bloodstream to form CTCs that are referred to as seeds to colonize and grow in soil-like distant target organs, while EVs of tumor and nontumor origin act as fertilizers in the process of tumor metastasis. There is no previous text that provides a comprehensive review of the role of EVs on CTCs during tumor metastasis. In this paper, we reviewed the mechanisms of EVs on CTCs during tumor metastasis, including the ability of EVs to enhance the shedding of CTCs, protect CTCs in circulation and determine the direction of CTC metastasis, thus affecting the distant metastasis of tumors.
ConDoR: tumor phylogeny inference with a copy-number constrained mutation loss model
Authors: Palash Sashittal, Haochen Zhang, Christine A. Iacobuzio-Donahue, Benjamin J. Raphael
Journal: Genome biology (2023)

Abstract A tumor contains a diverse collection of somatic mutations that reflect its past evolutionary history and that range in scale from single nucleotide variants (SNVs) to large-scale copy-number aberrations (CNAs). However, no current single-cell DNA sequencing (scDNA-seq) technology produces accurate measurements of both SNVs and CNAs, complicating the inference of tumor phylogenies. We introduce a new evolutionary model, the constrained k -Dollo model , that uses SNVs as phylogenetic markers but constrains losses of SNVs according to clusters of cells. We derive an algorithm, ConDoR, that infers phylogenies from targeted scDNA-seq data using this model. We demonstrate the advantages of ConDoR on simulated and real scDNA-seq data.
Reactive oxygen species (ROS) scavenging biomaterials for anti-inflammatory diseases: from mechanism to therapy
Authors: Jiatong Liu, Xiaoyue Han, Tingyue Zhang, Keyue Tian, Zhaoping Li, Feng Luo
Journal: Journal of Hematology & Oncology (2023)

Inflammation is a fundamental defensive response to harmful stimuli, but the overactivation of inflammatory responses is associated with most human diseases. Reactive oxygen species (ROS) are a class of chemicals that are generated after the incomplete reduction of molecular oxygen. At moderate levels, ROS function as critical signaling molecules in the modulation of various physiological functions, including inflammatory responses. However, at excessive levels, ROS exert toxic effects and directly oxidize biological macromolecules, such as proteins, nucleic acids and lipids, further exacerbating the development of inflammatory responses and causing various inflammatory diseases. Therefore, designing and manufacturing biomaterials that scavenge ROS has emerged an important approach for restoring ROS homeostasis, limiting inflammatory responses and protecting the host against damage. This review systematically outlines the dynamic balance of ROS production and clearance under physiological conditions. We focus on the mechanisms by which ROS regulate cell signaling proteins and how these cell signaling proteins further affect inflammation. Furthermore, we discuss the use of potential and currently available-biomaterials that scavenge ROS, including agents that were engineered to reduce ROS levels by blocking ROS generation, directly chemically reacting with ROS, or catalytically accelerating ROS clearance, in the treatment of inflammatory diseases. Finally, we evaluate the challenges and prospects for the controlled production and material design of ROS scavenging biomaterials.
The exon-junction complex helicase eIF4A3 holds therapeutic potential in acute myeloid leukemia
Authors: Sophia Miliara, Elisabetta Cozzi, Xiangfu Zhong, Isaac Chan, Karl Ekwall, Sören Lehmann, Andreas Lennartsson, Jiri Bartek, Dimitris C. Kanellis
Journal: Leukemia (2023)
Correction: Preclinical development of 1B7/CD3, a novel anti-TSLPR bispecific antibody that targets CRLF2-rearranged Ph-like B-ALL
Authors: Ze Tian, Chunhua Shi, Guojun Yang, Jason K. Allen, Qing Shi, Amin AL-Shami, Jill Wardell Olson, Melinda G. Smith, Qing Chang, Jasbir Kaur, Junping You, Timothy E. Lofton, Michelle A. Gonzalez, Qi Zhang, DongXing Zha, Sarah K. Tasian, Nitin Jain, Marina Y. Konopleva, Timothy Heffernan, Jeffrey J. Molldrem
Journal: Leukemia (2023)
Zero-shot interpretable phenotyping of postpartum hemorrhage using large language models
Authors: Emily Alsentzer, Matthew J. Rasmussen, Romy Fontoura, Alexis L. Cull, Brett Beaulieu-Jones, Kathryn J. Gray, David W. Bates, Vesela P. Kovacheva
Journal: npj Digital Medicine (2023)

Abstract Many areas of medicine would benefit from deeper, more accurate phenotyping, but there are limited approaches for phenotyping using clinical notes without substantial annotated data. Large language models (LLMs) have demonstrated immense potential to adapt to novel tasks with no additional training by specifying task-specific instructions. Here we report the performance of a publicly available LLM, Flan-T5, in phenotyping patients with postpartum hemorrhage (PPH) using discharge notes from electronic health records ( n = 271,081). The language model achieves strong performance in extracting 24 granular concepts associated with PPH. Identifying these granular concepts accurately allows the development of interpretable, complex phenotypes and subtypes. The Flan-T5 model achieves high fidelity in phenotyping PPH (positive predictive value of 0.95), identifying 47% more patients with this complication compared to the current standard of using claims codes. This LLM pipeline can be used reliably for subtyping PPH and outperforms a claims-based approach on the three most common PPH subtypes associated with uterine atony, abnormal placentation, and obstetric trauma. The advantage of this approach to subtyping is its interpretability, as each concept contributing to the subtype determination can be evaluated. Moreover, as definitions may change over time due to new guidelines, using granular concepts to create complex phenotypes enables prompt and efficient updating of the algorithm. Using this language modelling approach enables rapid phenotyping without the need for any manually annotated training data across multiple clinical use cases.